Discovery and SAR of 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide: A potent inhibitor of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer

We have developed a series of cyclic amine-containing benzimidazole carboxamide poly(ADP-ribose)polymerase (PARP) inhibitors, with good PARP-1 enzyme potency, as well as cellular potency. These efforts led to the identification of a lead preclinical candidate, 10b, 2-(1-propylpiperidin-4-yl)-1H-benz...

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Published inBioorganic & medicinal chemistry Vol. 16; no. 14; pp. 6965 - 6975
Main Authors Penning, Thomas D, Zhu, Gui-Dong, Gandhi, Viraj B, Gong, Jianchun, Thomas, Sheela, Lubisch, Wilfried, Grandel, Roland, Wernet, Wolfgang, Park, Chang H, Fry, Elizabeth H, Liu, Xuesong, Shi, Yan, Klinghofer, Vered, Johnson, Eric F, Donawho, Cherrie K, Frost, David J, Bontcheva-Diaz, Velitchka, Bouska, Jennifer J, Olson, Amanda M, Marsh, Kennan C, Luo, Yan, Rosenberg, Saul H, Giranda, Vincent L
Format Journal Article
LanguageEnglish
Published England 15.07.2008
Subjects
Animals
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Benzimidazoles - chemistry
Benzimidazoles - pharmacology
Breast Neoplasms - drug therapy
Cisplatin - therapeutic use
Dacarbazine - analogs & derivatives
Dacarbazine - therapeutic use
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Melanoma, Experimental - drug therapy
Mice
Poly(ADP-ribose) Polymerase Inhibitors
Structure-Activity Relationship
Transplantation, Heterologous
Xenograft Model Antitumor Assays
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Summary:We have developed a series of cyclic amine-containing benzimidazole carboxamide poly(ADP-ribose)polymerase (PARP) inhibitors, with good PARP-1 enzyme potency, as well as cellular potency. These efforts led to the identification of a lead preclinical candidate, 10b, 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide (A-620223). 10b displayed very good potency against both the PARP-1 enzyme with a K(i) of 8nM and in a whole cell assay with an EC(50) of 3nM. 10b is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast xenograph model in combination with cisplatin.
Bibliography:ObjectType-Article-1
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ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.05.044